The focus of this proposal is to elucidate molecular mechanisms of cartilage and bone formation. Identification of the specific molecules involved in skeletal morphogenesis may suggest treatments for degenerative diseases of the skeleton, and lead to improved methods for diagnosis and treatment of genetic disorders. Understanding mechanisms of skeletal development may serve as a paradigm for similar studies in other systems. A model will be proposed which incorporates 1) recent discoveries identifying genes critical for skeletal morphogenesis 2) characteristics of signalling pathways involving these genes 3) preliminary results describing mice which contain a null mutation in Indian hedgehog (Ihh), a gene crucial for normal skeletal development. The predictions of this model will be tested by characterizing the histology, phenotype, and patterns of expression of Parathyroid Hormone- related Protein (PTHrP), Bone Morphogenetic Protein (BMP), Patched, and Gli in the Ihh mutant. Two sets of double mutants will then be produced by simple intercross and examined to further clarify the relationship between Ihh, PTHrP, BMP, and Noggin.